Journal of Ethnopharmacology 279 (2021) 114342
Available online 19 June 2021
0378-8741/© 2021 Elsevier B.V. All rights reserved.
A systematic review with meta-analysis on the antihypertensive efficacy of
Nigerian medicinal plants
Mansurah A. Abdulazeez a, Suleiman Alhaji Muhammad b,*, Yusuf Saidu b, Abdullahi B. Sallau c,
Auwalu A. Arzai d, Musa Abdulkadir Tabari e, Abubakar Hafiz f, Muhammad Yalwa Gwarzo g,
Jiradej Manosroi h, Aminu Idi f, Musa Bashir i, Shamsudeen L. Pedro a
a Centre for Biotechnology Research, Bayero University, Kano, Nigeria
b Department of Biochemistry, Usmanu Danfodiyo University Sokoto, Nigeria
c Department of Biochemistry, Faculty of Life Sciences, Ahmadu Bello University, Zaria, Nigeria
d Department of Microbiology, Faculty of Science, Bayero University, Kano, Nigeria
e Department of Radiology, Barau Dikko Teaching Hospital (BDTH), Kaduna State University (KASU), Kaduna, Nigeria
f Department of Biochemistry, Faculty of Basic Medical Sciences, Bayero University, Kano, Nigeria
g Department of Medical Laboratory Science, Faculty of Allied Health Sciences, College of Health Sciences, Bayero University, Kano, Nigeria
h Department of Cosmetic Technology, Faculty of Engineering, North-Chiang Mai University, Chiang Mai, Thailand
i Centre for Dryland Agriculture, Bayero University, Kano, Nigeria
A R T I C L E I N F O
Keywords:
Nigerian medicinal plants
Hypertension
Systolic and diastolic pressure
Preclinical studies
Clinical trials
A B S T R A C T
Ethnopharmacological relevance: Despite the promising effects of herbal preparations in lowering blood pressure
(BP), hypertension remains a major clinical challenge in Nigeria. The BP-lowering effects of medicinal plants are
due to the presence of bioactive compounds.
Aim of the study: This meta-analysis presents a precise estimate of the therapeutic benefits of medicinal plants
utilized in Nigeria for the management of hypertension in animals and humans.
Methods: A systematic literature search was performed through Cochrane, PubMed, Science Direct and Scopus
databases from inception until February 28, 2021 using search terms related to randomized controlled trials of
Nigerian medicinal plants for hypertension. Additional studies were identified through manual search. BP was
the main outcome that was measured after the intervention. Meta-analysis was performed using the Review
Manager and Meta-Essential.
Results: Nineteen trials comprising of 16 preclinical and 3 clinical studies were enrolled for the meta-analysis. A
total number of 16 plants was identified of which H. sabdariffa was the highest reported plant. The plant extracts
significantly lowered the systolic blood pressure (SBP) and diastolic blood pressure (DBP) of the hypertensive
subjects compared to control. Weighted mean difference (WMD) for SBP (−43.60 mmHg, 95% CI: −63.18,
−24.01; p<0.0001) and DBP (-29.50 mmHg, 95 CI: −43.66, −15.34; p<0.0001) was observed for the preclinical
studies. For clinical trials, the WMD was −13.98 mmHg, 95 CI: −19.08, −8.88; p<0.00001 for SBP and −10.00
mmHg, 95 CI: −12.22, −7.78; p<0.00001 for DBP. High heterogeneity was observed for the outcome measures
of preclinical studies, but not for the clinical studies. The observed substantial heterogeneity in preclinical studies
may be linked to methodological shortcomings as evidenced by the results of the risk of bias assessment. There
was no evidence of publication bias in animal trials for BP using the funnel plot and Egger’s regression test (SBP,
p=0.239 and DBP, p=0.112).
Conclusions: This study provides evidence of medicinal preparations for the treatment of hypertension. A well-
conducted trial with methodological rigour and a longer duration of follow-up is required for their effective
clinical utilization.
Abbreviations: BP, blood pressure; CPT, cold pressor test; DBP, diastolic blood pressure; DF, diet formulation; DM, diabetes mellitus; DOCA, deoxycorticosterone
acetate; HGE, handgrip exercise; L-NAME, N-nitro-L-arginine methyl ester; MeOH, methanol; MD, mean difference; NO, nitric oxide; OS, oxidative stress; ROS,
reactive oxygen species; SD, standard deviation; SEM, standard error of the mean; SHR, spontaneously hypertensive rat; SBP, systolic blood pressure; WMD, weighted
mean difference.
* Corresponding author.
E-mail addresses: suleiman.muhammad@udusok.edu.ng, smbinna98@gmail.com (S.A. Muhammad).
Contents lists available at ScienceDirect
Journal of Ethnopharmacology
journal homepage: www.elsevier.com/locate/jethpharm
https://doi.org/10.1016/j.jep.2021.114342
Received 9 March 2021; Received in revised form 16 April 2021; Accepted 14 June 2021
Journal of Ethnopharmacology 279 (2021) 114342
2
1. Introduction
Hypertension is a chronic disease that is a risk factor for cardiovas-
cular and cerebrovascular diseases, resulting in clinical complications
such as stroke, heart failure, metabolic syndrome and renal dysfunction
(Bilbis et al., 2012; Muhammad et al., 2012; Shi et al., 2019). Obesity,
physical inactivity, smoking and high salt intake are the various pre-
disposing factors that have been implicated in the pathophysiology of
hypertension. Current evidence suggests that there is a connection be-
tween hypertension and continued endothelial damage. Endothelial
dysfunction is the inability of the endothelium to control vascular ho-
meostasis that can lead to a functional imbalance in favour of vaso-
constriction, pro-thrombosis and inflammation. The consequential effect
of which could lead to cardiovascular diseases and complications
(Roberts and Porter, 2013). Oxidative stress (OS) which is due to the
excess generation of reactive oxygen species (ROS) and inflammation
are the various mechanistic ways that have been implicated in the
development of hypertension (Muhammad et al., 2012; Rodrigo et al.,
2011). ROS is capable of diminishing nitric oxide bioavailability, a
factor that plays a significant role in maintaining healthy endothelium.
Therefore, treatment strategies targeting these factors could play
important roles in combating complications of hypertension.
The results of our previous study support the hypothesis linking
oxidative stress to hypertension (Saidu et al., 2012). In this study,
formulated antioxidant-rich nutraceutical from plant sources decreased
OS, increased NO bioavailability and improved the antioxidant status of
hypertensive rats, leading to a significant reduction in blood pressure.
This shows that plants could be explored as natural sources of bioactive
compounds for the treatment of hypertension. Furthermore, these plants
have been harnessed and are continually being explored for the devel-
opment of pharmaceutical drugs. It is, therefore, important that research
into the efficacy of these medicinal plants would help developing
countries, including Nigeria to develop new and safer medicinal rem-
edies for hypertension and other chronic diseases.
Consistent with this observation, several studies have reported me-
dicinal herbs as therapeutics for various diseases, including hyperten-
sion (Isari et al., 2019; Kim et al., 2018). Nigeria is not left out as studies
have indicated that medicinal plants are rich sources of natural bioactive
substances for the treatment of diseases (Gbolade, 2012; Salihu Shinkafi
et al., 2015). Despite the use of herbs as an alternative to conventional
drugs for the treatment and management of hypertension, the disease is
still a major health challenge in Nigeria. Medicinal plants have played a
significant role in the survival benefits of hypertensive patients due to
the inherent bioactive phytochemicals such as flavonoids, phenolics,
minerals and vitamins that are capable of exerting therapeutic and
curative effects. However, reports on meta-analysis of the efficacy of
Nigerian medicinal plants for the treatment of hypertension are scarce.
In this systematic review and meta-analysis, we investigated the anti-
hypertensive efficacy of Nigerian medicinal plants, with a view of
identifying the most used plant(s), their safety and the quality of the
studies that reported the use of these plants. This study included clinical
trials as well as preclinical studies that utilized plants from Nigeria for
the treatment of hypertension.
1.1. Review questions
This meta-analysis was performed to answer the following questions
related to Nigerian medicinal plants for the treatment of hypertension.
i. Would plant extracts be effective in lowering the blood pressure of
hypertensive subjects compared to control?
ii. Would plant extracts be safe as herbal remedies for hypertension?
2. Methods
2.1. Protocol
The updated Preferred Reporting Items for Systematic Reviews and
Meta-analyses (PRISMA) guidelines were followed in conducting this
systematic review (Page et al., 2021). The protocol of this study was
registered in PROSPERO with registration number: CRD42021232162.
2.2. Literature search
Cochrane, PubMed, Science Direct and Scopus databases were
searched without restriction on publication date until February 28, 2021
using the following terms: ‘Nigerian medicinal plants’ OR ‘medicinal
plants’ AND ‘hypertension’ OR ‘high blood pressure’ AND ‘humans’ OR
‘animal trials’. The eligibility studies were both clinical and preclinical
studies that utilized plants sourced from Nigerian for the treatment of
hypertension. Placebo or hypertensive subjects treated with the vehicle
or drug were the control group. A manual search of the reference list was
carried out to supplement the electronic search. Exclusion criteria were
studies that used medicinal plants not sourced from Nigeria, studies
without a comparator or the blood pressure parameters in the study
design and studies that used Nigerian medicinal plants on disease con-
ditions other than hypertension.
2.3. Outcome measures
Primary outcome measures were blood pressure (BP) parameters i.e.
systolic blood pressure (SBP) and diastolic blood pressure (DBP)
measured after the intervention. The secondary outcome measure was
the adverse event or toxicity reported during and/or after the treatment.
2.4. Data extraction and synthesis
Three independent reviewers (SAM, MAA &YS) retrieved the data
from the included studies using a predefined extraction spreadsheet and
disagreements were resolved through discussion and consensus or by a
third reviewer (ABS/AAA/MAT/JM). The details extracted from the
studies include authors’ name, year of publication, age, sex, weight, type
of plants, extraction solvent, dose, route of administration, duration of
the study, sample size, induction agent for preclinical studies, sample
size estimation and power analysis. Data for studies with more than one
dose, plant extract or model (preclinical) were combined and the
average was used for the meta-analysis. Quantitative data such as mean
and standard deviation (SD) or standard error of the mean (SEM) pre-
sented in figures were extracted using a highly magnified image soft-
ware (GetData Graph Digitizer, Version 2.26). SEM was converted to SD
using the following formula: SD = SEM ×
̅̅̅n
√ , where n is the number of
subjects.
3. Methodological quality assessment
Cochrane risk of bias tool for randomized controlled trials was used
to assess the risk of bias and was evaluated by three independent re-
viewers (SAM, YS & AH). Disagreements were resolved by consensus or
by consulting a third reviewer (MYG/AI/MB/SLP) The following do-
mains: selection bias, performance bias, detection bias, attrition bias,
reporting bias and other bias were assessed and rated as low, high or
unclear risk of bias.
3.1. Data analysis
A random-effects model was used for the meta-analysis of the pri-
mary outcome measures and heterogeneity was assessed with the I2
statistic. The mean effect size, 95% CI, forest plot and significance were
assessed using the inverse-variance method. Mean difference (MD) was
M.A. Abdulazeez et al.
Journal of Ethnopharmacology 279 (2021) 114342
3
used for the analysis of SBP and DBP. Values of I2 greater than 75% was
regarded as high heterogeneity. To evaluate the potential source of
heterogeneity and strength of the result, a subgroup and sensitivity
analysis were performed. Only groups with n ≥ 2 were included in the
subgroup analysis. Meta-analysis was performed using the Review
Manager (version 5.3), whereas Meta-Essential was used for Egger’s
regression test.
3.2. Publication bias
Publication bias was assessed using a funnel plot. Egger’s regression
asymmetry was also performed to confirm the results of the funnel plot
as previously reported (Egger et al., 1997).
4. Results
4.1. Selection of studies
A total of 1622 studies was identified from Cochrane, PubMed, Sci-
ence Direct and Scopus databases. Additional 23 studies were identified
through manual search. The full-text articles assessed for eligibility were
35. Out of 35 eligible articles, 28 (23 preclinical and 5 clinical studies)
met the inclusion criteria and were included in the review. The
remaining 7 articles were excluded due to the following reasons; Plant
not sourced from Nigeria or no detail (n=2), diabetes mellitus (n=1), not
plant extract (n=2) and no BP parameters (n=2). The description of the
search strategies is presented in Fig. 1.
4.2. Depiction of study characteristics
The characteristics of included studies showed that different plant
extracts were used for the intervention and these are depicted in Table 1.
In this systematic review, 19 out of the 28 studies that met the inclusion
criteria were enrolled for the meta-analysis involving 16 preclinical and
3 clinical studies. The total number of plants utilized were 16 from both
the animal and clinical studies.
4.3. Preclinical studies
The results of the animal studies indicated that H. sabdariffa was
reported in 4 studies (Balogun et al., 2019; Mojiminiyi et al., 2007,
2012; Onyenekwe et al., 1999), 3 studies were on Z. officinale (Akinyemi
et al., 2016a, 2016b; Tende et al., 2015), 2 studies each used
P. Americana (Imafidon and Fabian, 2010; Nwaefulu et al., 2009), C.
longa (Akinyemi et al., 2016a, 2016b), V. doniana (Ladeji et al., 1996;
Ogbeche et al., 2001), and A. sativum (Nwokocha et al., 2011; Tende
et al., 2015). M. cecropioides (Adeneye et al., 2006), B. coccineus (Akin-
dele et al., 2014), V. album (Eno et al., 2004), P. amarus (Amaechina and
Omogbai, 2007), M. flagellipes (Jovita et al., 2017), E. camaldulensis
(Nwaogu et al., 2018), N. latifolia (Nworgu et al., 2008), L. bengwensis
(Obatomi et al., 1996), P. curatellifolia (Omale et al., 2011), V. amyg-
dalina (Oyema-Iloh et al., 2018) and E. guineensis (Nkanu et al., 2019)
were each reported in 1 study. The part of the plants used for extraction
includes leaf, root, calyx, stem bark, rhizome and bulb, respectively.
Water (18 studies) was the most reported solvent that was used for the
extraction, followed by ethanol (3 studies), then methanol (2 studies)
and 1 study reported hydro-ethanol as the extraction solvent. The
duration of studies varies across the studies, ranging from a minimum of
8 days to a maximum of 18 weeks. Similarly, the dose administered to
the animals differs across the studies. The dosage range was between
0.0005 and 1000 mg/kg body weight. Different strategies were
employed in the induction of hypertension. It was observed that 8% salt,
N-nitro-L-arginine methyl ester (L-NAME) (40 and 50 mg/kg), 35%
ethanol, 7% sucrose and 15 mg of deoxycorticosterone acetate (DOCA)
were the various inducing agents used for the induction of hypertension.
Nephrectomy was also reported as the induction strategy. The summary
of study characteristics is depicted in Table 1.
4.4. Clinical studies
The results of clinical trials (Table 1) showed that the extract from
H. sabdariffa was reported in 4 (Aliyu et al., 2014; Nwachukwu et al.,
2015a, 2015b, 2017) out of the 5 studies included in this meta-analysis,
whereas P. americana was reported in 1 study (Olaniyan, 2014). Four
studies reported water as the solvent for extraction and the fifth study
adopted a crushing strategy to release the liquid from the leaf for
administration. The minimum dosage was 15 mg/kg, whereas 150
mg/kg was the maximum reported dose for the administration to the
subjects. Calyx and leaf.were the parts of the plant utilized for the
extraction of bioactive compounds.
4.5. Risk of bias assessment
The methodological rigour of the included studies was evaluated
using the Cochrane risk of bias tool for randomized controlled trials
(Higgins et al., 2011). The overall risk of bias of the included studies
ranges from moderate to high risk of bias, as most of the important
details were not reported in the included studies. It was observed that
only a few studies mentioned the randomization of subjects without
giving details. Furthermore, the allocation concealment, incomplete
outcome data, selective reporting and other risks of bias domains were
judged as low and unclear in most of the included studies because the
details required for these domains were reported. However, domains of
blinding of participants and outcome assessment were rated as high risk
of bias in almost all the included trials, as the details for these domains
were not reported. Only one study reported sample size estimation and
power analysis (Nwachukwu et al., 2015a). The risk of bias of individual
studies of preclinical and clinical trials is shown in Fig. 2a–b, whereas
the overall risk of bias of the domains assessed is depicted in Fig. 3a–b.
4.6. Systolic and diastolic pressure
4.6.1. Preclinical trials
The result of the effect of medicinal plant extract on SBP was re-
ported in 16 studies, involving 202 animals (Fig. 4a). When the hyper-
tensive animals were treated with the extract, a significant reduction in
SBP was observed in favour of the treated group with MD of −43.60
mmHg, 99% CI: −63.18, −24.01; p<0.0001. However, significant het-
erogeneity was observed across the studies (I2 = 99%; p<0.00001),
Fig. 1. Flow chart of the trial search process. DM-diabetes mellitus, BP –
blood pressure.
M.A. Abdulazeez et al.
Journal of Ethnopharmacology 279 (2021) 114342
4
suggesting there was a variation in the outcome measures between
studies. Treatment of the animals with the extract also reduced DBP
(−29.50 mmHg, 95 CI: −43.66, −15.34; p<0.0001) with substantial
heterogeneity between the studies (I2 = 98%; p<0.00001). The number
of studies included in the analysis was 14 studies that utilized 81 animals
(Fig. 4b).
4.7. Clinical studies
The effects of plant extract on SBP and DBP on hypertensive subjects
are presented in Fig. 5a and b. Three studies that used extracts from
H. sabdariffa were enrolled for the meta-analysis, involving 140 subjects.
Treatment of hypertensive patients with the extract of H. sabdariffa
significantly reduced SBP compared to control subjects (−13.98 mmHg,
95 CI: −19.08, −8.88; p<0.00001) with non-significant heterogeneity
(I2 = 55%; p=0.11) between the studies. Similarly, H. sabdariffa
significantly reduced DBP of hypertensive subject when compared with
control subjects (−10.00 mmHg, 95 CI: −12.22, −7.78; p<0.00001)
with homogeneity (I2 = 0%; p=0.40) between studies. A subgroup
analysis was not performed for clinical studies because there was a
similarity in outcome measures between the included studies.
4.8. Adverse event
This outcome was planned a priori as the secondary outcome mea-
sure. The results showed that the plant extracts were safe as no cases of
Table 1
Characteristics of included studies.
Author & Year
Plant type & part
Solvent for
extraction
Age/weight/sex
Induction agent/specie
Dose & treatment
route
Sample
size
Duration of
the study
Preclinical studies
Adeneye et al.
(2006)
M. cecropioides/stem bark
Water/hot
10–12 wk/
150–200 g/M & F
Rat
0.0005–0.05 mg/kg/
IV
30
–
Akindele et al.
(2014)
B. coccineus/leaf
Hydro-
ethanol/cold
150 g/M & F
35% ethanol & 5–7%
sucrose/rat
100,200, 400 mg/
kg/Oral
66
8 wk
Akinyemi et al.
(2016a)
Z. officinale.& C. longa/
rhizome
–
200–300 g/M
40 mg/kg l-NAME/rat
4% DF/oral
70
13 wk 3 d
Akinyemi et al.
(2016a)
Z. officinale.& C. longa/
rhizome
–
200–300 g/M
40 mg/kg l-NAME/rat
4% DF/oral
70
24 d
Amaechina &
Omogbai (2007)
P. amarus/leaf
Water/hot
1.2–2 kg
Rabbit
5–80 mg/kg IV
–
–
Anaka et al. (2009)
P. americana/seed
Water/cold
235–285 g/M
Rat
240, 260, 280 mg/
kg/oral
10
10 d
Balogun et al. (2019)
H. sabdariffa/leaf
Water/hot
10–12 wk/196.5
± 2.93 g/M
8% salt/rat
100, 200 & 400 mg/
kg/oral
25
6 wk
Eno et al. (2004)
V. album/leaf
Water/hot
200–250 g/M
15 mg/100g DOCA/rat
5–160 mg/kg/IV
10
6 wk
Etah et al. (2019)
E. guineensis/oil
180–250 g/M
Rat
15% oil
60
18 wk
Imafidon &
Amaechina (2010)
P. Americana/seed
Water/cold
–
8% salt/rat
200, 500,700 mg/kg
30
4 wk
Jovita et al. (2017)
M. flagellipes/seed
Ethanol/hot
100–200 g/M
Rat/8% salt +1% salt in
water
25, 50, 100 mg/kg/
oral
30
3 wk
Ladeji et al. (1996)
V. doniana/stem bark
Water/cold
250–300 g/F
Rat
200–800 mg/kg/oral
& IV
24
–
Mojiminiyi et al.
(2007)
H. sabdariffa/calyx
Water/hot
208.2±8.2 g/M
8% salt & 50 mg/kg L-
NAME/rat
1–125 mg/kg/IV
18
–
Mojiminiyi et al.
(2012)
H. sabdariffa/calyx
Water/hot
112–140 g
8% salt/rat
6 mg/ml
40
12 wk
Nwaogu et al. (2018)
E. camaldulensis/stem bark
MeOH/cold
180–250 g/M & F
8% salt/rat
50, 100, 200 mg/kg/
oral
30
7 wk
Nwokocha et al.
(2011)
A. sativum/bulb
Water/cold
150–180 g/5–7
wk/M
2 kidney, 1-clip model/
rat
20 mg/ml/IV
12
–
Nworgu et al. (2008)
N. latifolia/root
Ethanol/hot
180–250 g/M
Nephrectomy
2.5–20 mg/kg IV
20
–
Obatomi et al.
(1996)
L. bengwensis/leaf
Water/hot
230 g
SHR
Oral
–
8 d
Ogbeche et al.
(2001)
V. doniana/seed
Water/cold
200–250 g
SHR
200, 400, 800 mg/kg
Oral & IV
48
8 d
Omale et al. (2011)
P. curatellifolia/bark
Ethanol/hot
–
Cat
1 mg/ml/IV
–
–
Onyema-Iloh et al.
(2018)
V. amygdalina/leaf
MeOH/cold
120–160 g/M
8% salt/rat
200, 400 mg/kg/oral
40
8 wk
Onyenekwe et al.
(1999)
H. sabdariffa/calyx
Water/hot
–
SHR
500, 1000 mg/kg/
Oral
30
8 wk
Tende et al. (2015)
A. sativum & Z. officinale/
rizhome & bulb
Water/cold
12–16 wk/
150–200 g
Cat
0.1–20 mg/ml/IV
4
–
Clinical studies
Aliyu et al. (2014)
H. sabdariffa/calyx
Water/hot
29.9±1.6 yr/
67.3±2.7 kg
CPT/HGE (Sokoto)
15 mg/kg/oral
20
2 h
Nwachukwu et al.
(2015a)
H. sabdariffa/calyx
Water/hot
31–70 yr
Hypertensive patient
(Enugu)
150 mg/kg Oral
75
5 wk
Nwachukwu et al.
(2015b)
H. sabdariffa/calyx
Water/hot
M & F
Hypertensive patient
(Enugu)
150 mg/kg/oral
90
4 wk
Nwachukwu et al.
(2017)
H. sabdariffa/calyx
Water/hot
35–68 yr/M & F
Hypertensive patient
(Enugu)
150 mg/kg oral
75
4 wk
Olaniyan (2014)
P. Americana/leaf
Crushing
≥45 yr/M & F
Hypertensive patient
(Oke-Ogun, Oyo)
60 ml/d
50
–
CPT- Cold pressor test, d-day, DF-diet formulation, DOCA-deoxycorticosterone acetate, F- female, HGE-handgrip exercise, L-NAME- N-nitro-L-arginine methyl ester, M-
male, MeOH- methanol, SHR-spontaneously hypertensive rat, wk-week.
M.A. Abdulazeez et al.
Journal of Ethnopharmacology 279 (2021) 114342
5
adverse effect was reported except one study that recorded mortality at a
higher dose of the extract (Onyenekwe et al., 1999).
4.9. Subgroup and sensitivity analyses
We performed subgroup analyses for preclinical studies to determine
the source of heterogeneity observed for the outcome measures. The
studies were stratified into plant type and duration of follow-up. For the
type of plant, the studies were subgrouped into 2 (H. sabdariffa and
Z. officinale/C. longa) (Fig. 6a). The result of SBP showed a significant
effect size with high heterogeneity between the studies (I2 = 84%;
p<0.0003) for H. sabdariffa. Similarly, there was significant heteroge-
neity for DBP of H. sabdariffa subgroup (I2 = 81%; p<0.001) (Fig. 6b).
Furthermore, a non-significant heterogeneity (I2 = 38%; p=0.20) on the
effect of Z. officinale/C. longa on SBP was observed (Fig. 6a). However,
there was no subgroup analysis on DBP for the Z. officinale/C.longa
subgroup because of a lack of sufficient data. The results of the duration
of the follow-up subgroup, which was stratified into ≤4 and ≥ 4 weeks
showed a huge variation on both the SBP (Fig. 6c) and DBP (Fig. 6d)
parameters, suggesting this subgroup did not have an effect on the
variation observed on the outcome measures. To ascertain the robust-
ness of the estimated pooled effect size of the outcomes, we also
Fig. 2a. Risk of bias assessment in individual preclinical trials.
Fig. 2b. Risk of bias assessment in individual clinical trials.
Fig. 3a. Risk of bias item presented as percentages across the preclinical trials.
M.A. Abdulazeez et al.
Journal of Ethnopharmacology 279 (2021) 114342
6
performed a leave-one-out analysis to determine the source of hetero-
geneity observed between the studies. This was done by continually
removing one study at a time and recalculating the effect size of the
residual studies. It was observed that the heterogeneity was not
considerably changed for both SBP and DBP, suggesting that the varia-
tions between studies were not driven by any single study.
4.10. Publication bias
The publication bias was evaluated with a funnel plot and Egger’s
regression test. Visual inspection of the funnel plots of both the SBP
(Fig. 7a) and DBP (Fig. 7b) suggest no evidence of publication bias and
this was confirmed by Egger’s regression asymmetry. Results of Egger’s
regression test also showed no evidence of publication bias for SBP
(p=0.239) and DBP (p=0.112) in animal trials. According to Sterne et al,
(2011) at least 10 studies are required to detect the real chance of
asymmetry and as such publication bias was not performed for the
clinical studies.
5. Discussion
In developing countries, a large percentage of the population relies
on herbal medicines for primary health care. The use of herbs or eth-
nobotanicals as medicinal products is not only restricted to developing
countries as the industrialized nations have also developed interests in
natural therapies (Wachtel-Galor and Benzie, 2011) because of their
relative safety. The safety and efficacy of medicinal plants have been
evaluated in several studies, ranging from animal to clinical trials.
Therefore, this meta-analysis was conceived to assess the pooled effect
size of various plants that have been tested for the treatment of hyper-
tension in Nigeria. The primary outcome measures were the SBP and
DBP measured after the intervention, whereas safety was the secondary
outcome measure.
The result showed that the treatment of hypertensive subjects with
the plant extracts significantly reduced the SBP and DBP in both animal
and clinical studies. However, substantial heterogeneity was observed in
the animal studies, whereas a low heterogeneity was observed for the
outcome measures of clinical trials. The study revealed that extract from
16 different plants were utilized for the intervention in the trials with
H. sabdariffa being the highest number of plant extract. Secondary
metabolite such as phenolic, flavonoid, alkaloid, vitamins and others are
the various bioactive compounds that are responsible for the observed
therapeutic effects of the extract. Consistent with this observation,
various studies have shown that these bioactive compounds are capable
of lowering platelet aggregation, increase endothelium nitric oxide and
decrease oxidation of low density lipoproteins that are implicated in the
pathogenesis of hypertension (Apostolidou et al., 2015; de Figueiredo
et al., 2017; Luciano et al., 2011). We are not able to summarize the
safety outcome measure of the extracts because of a lack of meaningful
data. Although one study reported mortality at a higher dose of the
extract, the overall results of the included studies showed that the plant
extracts seem not causing adverse events or toxicities. Therefore, the
results of this meta-analysis demonstrate the efficacy and safety of these
medicinal plants in lowering blood pressure, indicating they can be
harnessed for the treatment of hypertension.
The methodological quality of the included studies showed that some
key elements were not reported, especially in animal studies. This
observation could be responsible for the high heterogeneity observed in
the outcome measures of these preclinical trials. Of all the studies
included in this systematic review, only one clinical trial reported a
priori sample size and power estimation. The study design in preclinical
trials has been faced with some methodological flaws over the years, and
this poses a threat to internal validity, which substantially affects the
translation to clinical trials. Therefore, effort must be geared towards
improving preclinical experimental design with methodological rigour
that would limit the threat to internal validity for effective translation to
Fig. 3b. Risk of bias item presented as percentages across the clinical studies.
Fig. 4a. Change in systolic blood pressure after intervention with the plant
extract in animal trials.
Fig. 4b. Change in diastolic blood pressure after intervention with the plant
extract in animal trials.
Fig. 5a. Effect size of intervention on systolic blood pressure in clinical trials.
Fig. 5b. Effect size of intervention on diastolic blood pressure in clinical trials.
M.A. Abdulazeez et al.
Journal of Ethnopharmacology 279 (2021) 114342
7
human studies.
Due to the high heterogeneity of the animal trials, we conducted
subgroup and sensitivity analyses of the outcome measures to determine
the strength of our results. The subgroup analyses of plant type and
duration of follow-up were conducted for the blood pressure. It was
observed that the overall results of subgroup analyses did not help in
detecting the source of heterogeneity. However, we did not conduct a
subgroup analysis on the dose, age and gender planned a priori due to
limited data to warrant the analysis. Similarly, a sensitivity analysis was
performed and the results indicated that the heterogeneity was not
driven by any single study.
The results of the funnel plot and Egger’s regression asymmetry in-
dicates no evidence of publication bias for the two outcome measures.
Taken together, this systematic review and meta-analysis present a
pooled effect size of the effectiveness of medicinal plant extracts in
lowering blood pressure of hypertensive subjects without any significant
adverse consequences. To the best of our knowledge, this is the first
meta-analysis of preclinical and clinical studies addressing the efficacy
of Nigerian medicinal plants for hypertension.
The positive findings of this meta-analysis should be interpreted in
light of the following limitations. First, the analysis of animal studies
had high heterogeneity between the studies and we were not able to
Fig. 6a. Preclinical subgroup of plant type on systolic blood pressure.
Fig. 6b. Preclinical subgroup of plant type on diastolic blood pressure.
Fig. 6c. Preclinical subgroup of the duration of follow-up on systolic blood pressure.
M.A. Abdulazeez et al.
Journal of Ethnopharmacology 279 (2021) 114342
8
detect the source of the variations despite the sensitivity and subgroup
analyses. This suggests that the studies have methodological weakness.
However, the results of human studies, although, very small in number
had shown low variation for SBP and homogeneity for DBP. Another
limitation of this current meta-analysis is that the study included is
limited to plant extracts sourced from Nigeria, which may introduce
selection bias and this may limit the generalization of evidence. How-
ever, strong methodological rigour as seen largely in clinical studies may
not limit the generalization of the results as the studies can be repro-
duced. Lastly, the studies were based on the crude extracts and this may
hinder the delineation of the exact mechanism(s) of their action in
lowering the blood pressure. Nevertheless, since the crude extracts are a
combination of different bioactive compounds could be acting in a
concerted manner to target different pathways that have been impli-
cated in the pathophysiology of hypertension.
5.1. Future directions
A favourable clinical outcome was observed following intervention
with the extracts; however, more studies are required to isolate and
characterize the active ingredient(s) responsible for the BP-lowering
effect. This would allow an insight into the mechanisms of action of
the bioactive constituents present in the extracts. A large randomized
clinical trial with the extracts, particularly the H. sabdariffa that have
shown promising results in human studies would guarantee the effective
clinical acceptance of this herb for the treatment and management of
hypertension. Clinical trials should be extended to other plant extracts
with methodological rigour to assess their efficacy in the treatment of
hypertension. Furthermore, standardizing the dosage of these extracts
are important determinants for their efficacy and safe clinical applica-
tion. Considering all these would provide evidence of the therapeutic
importance of ethnobotanical to combat hypertension and other related
diseases.
6. Conclusions
Herbal therapies hold promising effects in lowering the BP of hy-
pertensive subjects. This meta-analysis provides evidence of medicinal
herbs in the treatment of hypertension. The preclinical studies had
methodological shortcomings that required improvements that would
allow standardization of these herbal preparations for effective clinical
translation to treat hypertension. Even though H. sabdariffa improved
the clinical outcome of hypertensive patients, the number of studies is
small, hence large clinical trials with longer duration of follow-up are
Fig. 6d. Preclinical subgroup of the duration of follow-up on diastolic blood pressure.
Fig. 7. Funnel plot for changes in blood pressure. (a) Systolic blood pressure (b) Diastolic blood pressure. The results suggest no evidence of publication bias for both
outcome measures.MD-mean difference, SE-standard error.
M.A. Abdulazeez et al.
Journal of Ethnopharmacology 279 (2021) 114342
9
necessary for effective clinical utilization of these herbal remedies for
hypertension.
Authors’ contribution
Conceptualization: SAM, MAA, YS. Fund acquisition: MAA, YS, ABS,
AAA, MAT, AH, MYG, JM. Data curation: SAM, YS. Data analysis and
interpretation: SAM, YS, MAA. Writing- original draft: SAM, YS. Writing-
review & editing: MAA, ABS, AAA, MAT, AH, MYG, AI, MB, JM, SLP.
SAM, MAA & YS screened the articles & extracted data. ABS, AAA, MAT
& JM resolved disagreement in article inclusion and data extraction.
SAM, YS & AH evaluated the risk of bias. MYG, AI, MB & SLP settled
disagreement in the risk of bias assessment. All authors read and
approved this final version of the manuscript.
Declaration of competing interest
The authors declare that they have no conflicts of interest.
Acknowledgements
This research work was supported by a grant from the Tertiary Ed-
ucation Trust Fund, Nigeria with grant number: TETFUND/DR&D/CE/
NRF/STI/30/Vol1.
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